HMGB2 orchestrates the chromatin landscape of senescence-associated secretory phenotype gene loci

Aird, Katherine M.; Iwasaki, Osamu; Kossenkov, Andrew V.; Tanizawa, Hideki; Fatkhutdinov, Nail; Bitler, Benjamin G.; Le, Linh; Alicea, Gretchen M.; Yang, Ting; Johnson, F. Brad; Noma, Ken Ichi; Zhang, Rugang

doi:10.1083/jcb.201608026

Cited by 135 publications

(125 citation statements)

References 36 publications

(69 reference statements)

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“…Senescent cells also undergo chromatin reorganization, which is crucial for modulating gene expression, including SASP genes. For instance, Aird and colleagues have shown that high mobility group box 2 (HMGB2), which is a non‐histone chromatin‐bound protein that activates transcription by altering chromatin architecture, preferentially localizes to and upregulates SASP loci, including IL‐6 and IL‐8 . It should also be noted that the loss of HMGB2 during senescence represses SASP gene expression, but does not affect cell cycle arrest, consistent with the idea that senescence cell‐cycle arrest and SASP are regulated by different machineries .…”

Section: Regulation Of Sasp Inductionmentioning

confidence: 79%

Impact of senescence‐associated secretory phenotype and its potential as a therapeutic target for senescence‐associated diseases

et al. 2017

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“Cellular senescence” is a state in which cells undergo irreversible cell cycle arrest in response to a variety of cellular stresses. Once cells senesce, they are strongly resistant to any mitogens, including oncogenic stimuli. Therefore, cellular senescence has been assumed to be a potent anticancer mechanism. Although irreversible cell‐cycle arrest is traditionally considered the major characteristic of senescent cells, recent studies have revealed some additional functions. Most noteworthy is the increased secretion of various secretory proteins, such as inflammatory cytokines, chemokines, growth factors, and MMPs, into the surrounding extracellular fluid. These newly recognized senescent phenotypes, termed senescence‐associated secretory phenotypes (SASPs), reportedly contribute to tumor suppression, wound healing, embryonic development, and even tumorigenesis promotion. Thus, SASPs appear to be beneficial or deleterious, depending on the biological context. As senescent cells are known to accumulate during the aging process in vivo, it is quite possible that their accumulation in aged tissues promotes age‐associated functional decline and various diseases, including cancers, at least to some extent. Here, we focus on and discuss the functional and regulatory network of SASPs toward opening up new possibilities for controlling aging and aging‐associated diseases.

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Section: Regulation Of Sasp Inductionmentioning

confidence: 79%

Impact of senescence‐associated secretory phenotype and its potential as a therapeutic target for senescence‐associated diseases

et al. 2017

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“…Chromatin Immunoprecipitation (ChIP) assay was performed as previously described (Aird et al, 2016; Yokoyama et al, 2016). The following antibodies were used to perform ChIP: anti-BRD4 (Bethyl Laboratories), anti-RNA polymerase II (Santa Cruz).…”

Section: Methodsmentioning

confidence: 99%

BET Bromodomain Inhibition Synergizes with PARP Inhibitor in Epithelial Ovarian Cancer

et al. 2017

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Summary PARP inhibition is known to be an effective clinical strategy in BRCA-mutant cancers, but PARP inhibition has not been applied to BRCA-proficient tumors. Here we show synergy of BET bromodomain inhibition with PARP inhibition in BRCA-proficient ovarian cancers due to mitotic catastrophe. Treatment of BRCA-proficient ovarian cancer cells with the BET inhibitor JQ1 downregulated the G2-M cell cycle checkpoint regulator WEE1 and the DNA damage response factor TOPBP1. When combined with the PARP inhibitor Olaparib, we observed a synergistic increase in DNA damage and checkpoint defects, which allowed cells to enter mitosis despite the accumulation of DNA damage, ultimately causing mitotic catastrophe. Moreover, JQ1 and Olaparib showed synergistic suppression of growth of BRCA-proficient cancer in vivo in a xenograft ovarian cancer mouse model. Our findings indicate that a combination of BET inhibitor and PARP inhibitor represents a potential therapeutic strategy for BRCA-proficient cancers.

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“…It is known that DNA damage induces NF-κB signaling via a variety of signaling complexes containing the essential NF-κB modifier NEMO, as well as via the activation of the p38MAPK [23] and MK2 [24] signaling pathways. Genomic instability evoked by cellular stress triggers epigenetic changes, e.g., the high mobility group box 2 (HMGB2) proteins which orchestrate the chromatin landscape of SASP gene loci [25], and upregulation of SIRT1 expression which deacetylates NF-κB to blunt its transcriptional activity [26]. Further, the two cyclin-dependent kinase inhibitors, p16INK4a and p14ARF, are effective inhibitors of NF-κB signaling.…”

Section: Discussionmentioning

confidence: 99%

Membrane-Bound CD40L Promotes Senescence and Initiates Senescence-Associated Secretory Phenotype via NF-κB Activation in Lung Adenocarcinoma

Yuan

et al. 2018

Cell Physiol Biochem

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Background/Aims: Cellular senescence acts as a barrier against tumorigenesis. The CD40L transgene, expressed in some tumor cells, not only becomes visible to antigen-presenting cells but also actively catalyzes its own termination. Here, we evaluated the effect of a membrane-bound mutant form of human CD40L (CD40L-M) on senescence and the senescence-associated secretory phenotype (SASP) in non-small cell lung cancer (NSCLC). Methods: CD40 expression levels in the NSCLC cell lines A549/TR, A549/DDP and H460 were examined by flow cytometry. Senescent cells and tissues were identified via SA-β-gal activity. Cell proliferation was visualized by EdU labeling. qRT-PCR, Western blotting, and immunofluorescence staining were conducted to assess mRNA and protein expression levels of CD40L, γ-H2A.X, p65, p-p65, IκBα, p53, p21 and p16. Cytokines secreted from transfected cells were tested by ELISA and cell migration assay. Capsid tyrosine-modified rAAV5-CD40L-M was packaged and carried out in vivo. Results: Overexpression of CD40L-M promoted senescence, inhibited proliferation, increased DNA damage-associated γ-H2A.X, and initiated the SASP in CD40-positive NSCLC cells. NF-κB signaling was activated by CD40L-M overexpression in these cells. Knockdown of NF-κB partially overcame senescence and failed to induce SASP. Furthermore, increased p53 and p21 protein levels induced by CD40L-M were also reduced following NF-κB suppression. Conclusions: These data showed that the membrane-bound CD40L mutant may promote cellular senescence and initiate the SASP of NSCLC cells in an NF-κB-dependent manner. Therefore, CD40L-M-induced senescence may be a potential approach to protect against lung adenocarcinoma.

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HMGB2 orchestrates the chromatin landscape of senescence-associated secretory phenotype gene loci

Cited by 135 publications

References 36 publications

Impact of senescence‐associated secretory phenotype and its potential as a therapeutic target for senescence‐associated diseases

Impact of senescence‐associated secretory phenotype and its potential as a therapeutic target for senescence‐associated diseases

BET Bromodomain Inhibition Synergizes with PARP Inhibitor in Epithelial Ovarian Cancer

Membrane-Bound CD40L Promotes Senescence and Initiates Senescence-Associated Secretory Phenotype via NF-κB Activation in Lung Adenocarcinoma

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